European Journal of Pharmaceutical Sciences
18F-Radiolabeling and Preliminary Evaluation of a HSP90 ligand
,
*
,
,
P. Nordemana α, Z.P. Jayendraa α, E. Briardc, S.C. Lid, M. Larhedb, G. Antonia, S. Estradaa, R.
K. Selvarajua, O. Åberga, M.R. Jensene, P. Stålbergf, B. Skogseidd, A. Monazzamd
a Department of Medicinal Chemistry, BMC, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden
b Department of Medicinal Chemistry, Science for Life Laboratory, BMC, Uppsala University, Box 574, SE-751 23, Uppsala, Sweden
c Global Discovery Chemistry, Novartis Institutes for Biomedical Research, Novartis Pharma AG, Klybeckstrasse 141, 4057 Basel, Switzerland
d Department of Medical Sciences, Uppsala University, SE-751 05 Uppsala, Sweden
e Oncology, Novartis Institutes for Biomedical Research, Novartis Pharma AG, Klybeckstrasse 141, 4057 Basel, Switzerland
f Departments of Surgical Sciences, Uppsala University, SE-751 85 Uppsala, Sweden
A R T I C L E I N F O
A B S T R A C T
Keywords:
HSP90
Purpose: With the ambition of improving the management of pancreatic neuroendocrine tumors (P-NETs), we
developed and preliminary validated a novel fluorine-18 labelled HSP90 ligand.
PET
Methods: A precursor containing methoxymethyl ethers protecting groups and a tosyl as leaving group was
synthesized. The target compound was labeled with nucleophilic 18F-fluoride and the protecting groups was
subsequently removed with hydrochloric acid before purification. In vitro cell- and frozen section autoradiog-
raphy and in vivo animal studies were performed.
cancer
fluorine-18
Results: The precursor was successfully synthesized and utilized in the 18F-radiolabeling giving 0.5-1.0 GBq of
pure product with a synthesis time of 70 min. In vitro experiments indicated a high specific binding, but in vivo
studies showed no tumor uptake due to fast hepatobiliary metabolism and excretion.
Conclusions: Despite the unfavorable in vivo properties of the tracer, the promising results from in vitro auto-
radiography experiments in frozen sections of P-NETs from surgical resection encourage us to continue the
project aiming the improvement of in vivo properties of the tracer.
1. Introduction
are: narrow therapeutic window, patient selection and the design of
optimal dosing strategies, uncertainty whether the drug has reached the
Heat shock protein 90 (HSP90) is a chaperone that supports proper
folding of proteins, protects proteins against heat stress, and aids protein
degradation. Although HSP90 is expressed in all cells and tissues, cancer
cells exhibit increased HSP90 levels. Some tumors have been shown to
have higher-order multi-chaperone HSP90 containing complexes with
high affinity for HSP90 inhibitors, whereas normal tissues harbor latent,
uncomplexed HSP90 with low HSP90 inhibitor affinity. These findings
taken together with the ability of HSP90 to modulate many growth and
signaling pathways simultaneously has made HSP90 an attractive target
for cancer therapeutics (Yuno et al., 2018).
tumor and if it is actually affecting its target. The methods for the clinical
validation of HSP90 inhibitors consist of plasma sampling,
peripheral-blood mononuclear cells sampling, pre- and post-treatment
tumor biopsies (Whitesell et al., 2012). Some of the limitations of
these approaches are invasiveness, limited sample size, heterogeneity
and that the samples are not representative of the tumor. This empha-
sizes the need for predictive biomarkers that identify clinically relevant
responses and maximize efficacy and personalized treatment. One
approach is positron emission tomography (PET). PET is a non-invasive
method that is suitable to quantify uptake, concentration, clearance, and
distribution of an appropriately labeled agent in a comprehensive
manner. PET with radiolabeled targeted anticancer drugs provides
insight in target expression as well as intra-tumor drug accumulation
Despite the development of more than twenty clinically evaluated
HSP90 inhibitors, none is used in routine clinical practice (Shrestha
et al., 2016). Major obstacles for clinical success of the HSP90 inhibitors
Abbreviations: HSP, heat shock protein; P-NET, pancreatic neuroendocrine tumors; PET, positron emission tomography; DCM, dichloromethane; DMF, dime-
thylformamide; MeCN, acetonitrile.
* Corresponding author.
α
Both authors contributed equally to this manuscript.
Received 4 August 2020; Received in revised form 3 November 2020; Accepted 11 November 2020
Available online 20 November 2020
0928-0987/© 2020 Elsevier B.V. All rights reserved.
Nordeman
